Peer reviewed article Analytical and formulation attributes in developing generic sterile injectable liquid and lyophilized drugs (part 1) Arindam Roy ARINDAM ROY 1,2 *, GURMUKH CHANANA 1 *Corresponding author 1. Boehringer Ingelheim Ben Venue Laboratories, 300 Northfield Rd, Bedford, OH 44146 2. Current address: Oakwood Laboratories, 7670 first place, Oakwood village, OH 44146 78 ABSTRACT A generic drug manufacturer typically spends much less time preparing an Abbreviated New Drug Application (ANDA) than the New Drug Application (NDA) to establish equivalency to the innovator s product and allow access to the market. For a given drug product, the formulation information is often listed in the package insert of the branded drug, providing valuable formulation information to generic developers. In this two part article generic sterile injectable development processes are discussed. Part 1 of this article discusses several aspects of the development processes including deformulation, API selection, container closure, fi lter validation and product compatibility studies. INTRODUCTION A generic drug has the same active ingredient(s) as the reference listed drug (RLD) or branded drug. It also has the same dosage form, strength and conditions for use as the RLD. Approximately 60 percent of prescriptions in USA are now fi lled with generic drugs, and research shows that generics work as well as their branded counterparts. Generic manufacturers are able to sell products for lower prices, not because the products are of any lesser quality, but because the generic manufacturers generally do not engage in costly advertising and promotion or need to recoup the expense of drug design, development and multiphase clinical testing. The FDA reports very few adverse events related to specifi c generic drugs that are not related to known side effects of the drug ingredient itself (1). Generic drug development Understanding the chemistry and details of RLD is very critical to the development of good quality generic products. Using the materials listed on the RLD label without understanding the purpose of each ingredient present lead to problems later, such as investigation of out of specification results or other quality issues of the product. The FDA has also put emphasis on the development aspects of generic drugs and more detailed studies are expected to show the understanding and rationale of the formulation by the generic companies. With the full implementation of Quality by Design (QBD) from 2013 by the FDA, there will be an increased expectation of a detailed development report justifying the Critical Quality Attributes (CQAs) of the drug product. Apart from the FDA and ICH Guidelines, there are several technical reports available from the Parenteral Drug Association (2, 3) that is good source for various aspects of the development, manufacturing and commercialization of parenteral drug products. In general, the development of generic drug products has the following elements: 1) RLD Deformulation The deformulation of the RLD is the starting point for successful development of generic products. Although the package insert provides valuable information about the amount of certain ingredients present, it may not provide all the detailed information. The deformulation studies should include literature and patent reviews that provide the bulk of the information as to the choices of formulation and excipients used in the RLD. It also helps in identifying potential pitfalls of the product. Simple laboratory studies are done to establish the critical quality attributes (CQAs) for the product such as ph ranges and initial impurity profile. RLD analysis near the end of its shelf life is very critical in establishing the impurity specifications of the generic product. Evaluation of container closure used in RLD is helpful in determining suitable components for generic products. Examination of headspace oxygen content or in the case of a lyophilized product, the moisture content will help set the goal for formulation of the generic product. Establishing an understanding of the excipients used in the RLD will help in designing alternate formulations where an antioxidant, buffer system or preservatives may be changed. 2) Selection of Active Pharmaceutical Ingredients (API) Choosing an API supplier is a significant task in generic drug development since most of the generic companies do not have their own API development and manufacturing unit. If a firm is engaged in making a number of generic drugs, it is helpful to establish relationships with a few API suppliers, who are able to develop and supply a variety of API s. This can reduce the workload of going to several different suppliers and auditing and negotiating pricing with them. For sterile injectable generic drug development, the main quality attributes for an API are assay and impurity profile. Figure 1 depicts assay and impurity profiles with respect to the ICH/FDA/ European Medicines Agency (EMEA) guidelines and the separation technique commonly employed (4, 5). A particular polymorphic form is generally not that important in the quality attributes of the generic injectable development, however they may come into play from a patent perspective. Understanding and controlling the genotoxic impurities which may be present in an API is getting a lot of attention. One of the more recent developments in mass spectrometry, which is helpful in this process, is differential analysis software developed for use with LC-MS data. Differential analysis can be used to look for very small differences in samples such as the differences between two lots
of stability samples, differences in APIs from two different vendors, differences in products from different sources, etc. This kind of analysis is particularly important when minute differentiation among samples is required, such as in the determination of low level impurities. Mass profiler is one example of this kind of software. Figure 1. Assay and impurity profiles of APIs with respect to the FDA/ICH/EMEA guidelines and separation technique commonly employed. ICH Q3A addresses the quantitation and characterization of organic impurities in APIs. Organic and inorganic impurities include starting materials, by-products, intermediates, degradation products, reagents, residual solvents, heavy metals, inorganic salts and other materials. Quantitation of these impurities includes HPLC/UHPLC, while characterization includes LC-MS and/or GC-MS analysis. ICH Q3C sets guidelines for specific residual solvents that are usually determined by GC-FID or GC-MS. Impurities in the API must be classified and identified. The ICH guidance document sets thresholds for reporting, identification and quantification as shown in Table 1. When an impurity presents a probable toxicity risk or a specific structure alert, no new or higher levels of the impurity can be introduced as compared to products with existing market authorizations (1, 4). (PVDF), Polyethersulfone, Nylon, Polytetrafluoroethylene (PTFE) etc. The choice and selection of filter are based on the nature of the drug product, filtration systems in place and manufacturing process being used. The selected filter for the product undergoes a validation study that determines the suitability of the filter for the drug product. The validation studies include compatibility, bacterial retention, filter extractable, filter integrity and filter sizing studies. These studies may be done internally or contracted out with the filter vendors that provide these services. Filter compatibility may include effect of the drug formulation on the physical characteristics of the filter (cartridge or capsule). Bacterial retention testing for drug formulation is a critical step in filter validation required by all regulatory bodies worldwide. The United States Food and Drug Administration (FDA) guidance on sterile drug products produced by aseptic processing recommends that microbial retention testing be conducted using the drug product solution and simulated processing conditions; this validates sterilizing-grade filter performance. PDA s technical report 26 further outlines parameters to be considered and modelled during the testing process. Bacterial retention testing is done by evaluating the retention of test microorganism by sterilizing-grade membrane filters in the presence of drug product or surrogate fluid (when the drug product itself is bacteriostatic or bactericidal) at the proposed filtration conditions. Testing is conducted using worst-case processing conditions to determine the ability of a sterilizing-grade filter to retain a minimum challenge of 10 7 cells of Brevundimonas diminuta (B. diminuta) per cm 2 of filter area. Filter integrity test is a non destructive test employed during the filtration process. Filter integrity tests can be done pre-filtration and post filtration of the drug product, however only the post filtration integrity test on the filters is required by regulatory agencies as proof that the drug product was rendered sterile after filtration. The integrity test can be done using model solvents (water, IPA/water mixture, etc.) after flushing the filter with copious amounts of model solvent to remove all drug products prior to testing. However, drug product specific integrity values may also be obtained prior to manufacturing that can be used for routine monitoring. 79 Table 1. ICH Q3A Guidelines for Reporting, Identification and Qualification Threshold Limits of API. 3) Selection of Container Closure Although the majority of pharmaceutical parenteral drug products use Flint glass type I vials, these vials from various vendors may have small differences in composition of the glass. These differences may be small; however the drug product stability may be impacted by the levels of some components such as oxides of alkaline and alkaline earth metals that can potentially leach out over the shelf life. Stability studies with formulations developed in the laboratory in proposed container closures may be part of the study design to ensure the components are compatible with the product. Detailed reports with supporting data for container closure integrity are also required. Multiple tests (e.g. dye tests, helium leak tests etc.) are used to ascertain the container closure integrity. 4) Filter Validation Studies Filters are an integral part of the parenteral drug product manufacturing process. One or more 0.22 micron filters are used as final filters before the drug product is filled into ampoules, vials, syringes or cartridges. Therefore proper selection of filters and filter sizes that are compatible with the product need to be selected. There are several types of filters available in the market with membranes made of inert materials such as Polyvinylidene fluoride 5) Product Contact Parts Compatibility Studies Parenteral drug product comes in contact with several materials during manufacturing. Therefore, it is essential that compatibility studies with all product contact parts such as tubings and other equipment part materials, stainless steel and filter materials be evaluated to ensure that the drug product quality is maintained. The study design may be based on the maximum exposure time with product contact parts in the proposed manufacturing scheme. 6) Development of Formulation and Formulation Processes Once the API and excipients have been selected, one or more formulations with different excipients or varying concentration of excipients may be prepared in laboratory to gain understanding of the formulations. These formulations are analysed and the data may be compared to RLD data generation to build a rationale as well as robustness of the formulation. With new requirements for designing formulations and processes including QBD principles, it is important to use Design of Experiments (DOE) in developing formulations and formulation processes. Once the formulation composition of the drug product is established, development of the manufacturing process is initiated. The first step is to determine what sterilization process is to be used for the drug product. Sterile drug products are produced by either aseptic process or utilizing terminal sterilization. Terminal sterilization is a process whereby product is rendered sterile either by applying heat in an autoclave or by radiation (E-Beam or gamma-radiation). Aseptic process is a process whereby a product is passed through a microbial retentive filter in a clean environment and filled into a sterile container. Although terminal sterilization of the product is preferred as it provides higher level
of sterility assurance, aseptic process is appropriate when the product is susceptible to heat or the product is lyophilized. A good decision tree is available from EMEA (3) that can be used as guidance in selection of sterilization process. A typical manufacturing process flow for an Aseptic Process is given in Figure 2 and for Terminal Sterilization in Figure 3. compatibility studies. In the second part of this article, scale up considerations, lyophilization development, and analytical development will be discussed. Relevant USP/ICH guidelines with respect to the generic development will also be highlighted. ACKNOWLEDGEMENTS Figure 2. Manufacturing Process flow for Aseptically manufactured products. The input from various colleagues from the pharmaceutical industry at large are acknowledged, particularly the members of the Product and Process Development (PPD) department at Boehringer Ingelheim (BI) Ben Venue Laboratories. Many helpful discussions, encouragement, support and guidance provided by Dr. William Larkins is acknowledged. Finally, authors would like to thank Greg Fernengel and Michael Strozewski for reviewing and proofreading the article. DISCLAIMER The views provided in this articles are from the authors only and not from the Boehringer Ingelheim or any of its associates. 80 Figure 3. Manufacturing Process flow for terminally sterilized product. CONCLUSION Part 1 of this article discussed several aspects of the generic sterile injectable development processes including deformulation, API selection, container closure, filter validation and product REFERENCES AND NOTES 1. www.fda.gov 2. www.ich.org 3. Parenteral Drug Association http://www.pda.org/publications_1/ PDA-Publications/Technical-Reports.aspx 4. Arindam Roy et al., Analytical Strategies in the Development of Generic Drug Products: Role of Chromatography and Mass Spectrometry, Pittcon (2011). 5. www.ema.europa.eu